What can waning efficacy look or sound like?

Over time, repeated exposure to neurotoxins with complexing proteins can contribute to a decrease in treatment response.

Decreased Satisfaction1
Patients say the drug doesn't work as well as it used to
Increased Dosing1
Patients appear to require an increased dose in order to maintain efficacy or regain lost efficacy
Higher Frequency1
Patients are requesting shorter dosing intervals because they are experiencing decreased response
Loss of Patients
Patients feel less motivated to come back for reinjection or are lost to follow-up

Waning Efficacy and Neutralizing Antibodies

The clinical relevance of immunogenicity is primarily associated with the development of neutralizing antibodies (NAbs), which can lead to secondary non-responsiveness or a waning of clinical effect.

A pair of boxing gloves, wraps, and a mouthguard. These are meant to symbolize the complexing proteins found in XEOMIN

BoNT therapy is often lifelong in patients with chronic conditions; thus, the potential for immunogenicity and risk of reducing NAb production should be considered when making treatment decisions regarding BoNT formulation”1

 

WATCH IMMUNOLOGIST DR WARNER CARR DISCUSS THE IMPACT OF NAb ON TREATMENT RESPONSE

Signs of Waning Efficacy with Chronic, Long-term Exposure to Proteins in Neurotoxin Formulations

NAb formation does not occur in all patients, but because of its increasing likelihood with long-term neurotoxin use, it should be considered when starting or adjusting therapy.1

COMPLEXING PROTEINS MAY CONTRIBUTE TO NAb FORMATION

Up to 83% of the total protein mass in the illustration to the right has no therapeutic activity and may potentially increase the risk of waning efficacy over time.1-4
An illustration of complexing proteins: hemagglutinin, non-toxin, non-hemagglutinin, and core neurotoxin
Learn how XEOMIN is different

The direct impact of the non-therapeutic proteins on long-term safety or efficacy continues to be evaluated. Information about the unique XEOMIN manufacturing process and the properties of incobotulinumtoxinA is not intended to imply superiority over other botulinum toxin type A products.

There is a potential for immunogenicity with the use of any botulinum toxin formulation. This information is not meant to imply superiority of safety or efficacy of any toxin; differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies across products or studies. The effect of the presence or absence of antibodies on a product's safety or efficacy continues to be evaluated.

FDA, US Food and Drug Administration; NAbs, neutralizing antibodies.

An illustration of the XEOMIN molecule without complexing proteins
Designed with Purity in Mind

XEOMIN Contains Only the Active Neurotoxin1-3

The unique manufacturing process reduces the size of the XEOMIN molecule from 900 kDa to 150 kDa—approximately 6 times less mass.1-3

XEOMIN is developed using proprietary XTRACT Technology®—a state-of-the-art manufacturing process that removes complexing proteins.6

An illustration of the XEOMIN molecule without complexing proteins

In retrospective studies, NAbs were more likely to develop over time after treatment with a neurotoxin formulation with a higher molecular weight1-3

XTRACT Technology ®

Watch XTRACT Technology in Action

IN XEOMIN PIVOTAL STUDIES, PATIENTS DID NOT DEVELOP NAb-RELATED CLINICAL RESISTANCE TO XEOMIN

 

In more than 2600 patients treated with XEOMIN in pivotal clinical trials, there were no reports of waning efficacy due to NAb formation1,6

1490 adult patients were treated with XEOMIN. 1159 pediatric patients were treated with XEOMIN. 0 patients with clinical resistance to XEOMIN due to NAb

Of the patients treated with XEOMIN in clinical trials, 9 (0.3%) patients were positive for NAb after treatment whose antibody status at baseline was unknown, and 4 (0.2%) additional patients developed NAb after treatment. All of these patients were previously treated with onabotulinumtoxinA and/or abobotulinumtoxinA prior to enrollment in the studies. No patients in the Xeomin pivotal trials demonstrated a secondary lack of treatment response due to NAb.

In a separate, independent, monocenter, retrospective cohort study4

49 patients treated exclusively with XEOMIN. 0 reports of waning efficacy due to NAb. Average length of treatment 8.4 years

See the Science Behind XEOMIN: Mechanism of Action

Manufacturers use a selected strain of Clostridium botulinum, bred biologically in optimal conditions, to produce therapeutic botulinum toxin products.6

XEOMIN is a botulinum toxin type A that blocks transmission at the neuromuscular junction by inhibiting the release of ACh from peripheral cholinergic nerve endings.6

In both muscle and glands, impulse transmission is reestablished by the formation of new nerve ends.6

See the head-to-head studies

The direct impact of the non-therapeutic proteins on long-term safety or efficacy continues to be evaluated. Information about the unique XEOMIN manufacturing process and the properties of incobotulinumtoxinA is not intended to imply superiority over other botulinum toxin type A products.

Neutralization is possible with all neurotoxins, including XEOMIN.

The potency Units of XEOMIN are specific to the preparation and assay method utilized. They are not interchangeable with the other preparations of botulinum toxin products and, therefore, Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method.

NAbs, neutralizing antibodies; ACh, acetylcholine.

Consistently Demonstrated in Head-to-Head Studies

Noninferiority: XEOMIN vs active comparator (BOTOX)

XEOMIN and Botox (onabotulinumtoxinA) were proven safe and effective in treating the symptoms of cervical dystonia as measured by the TWSTRS score at Week 4, and blepharospasm as measured by the JRS sum score at Week 3.7,8

The corner rope of a boxing ring. This is meant to symbolize the noninferiority between XEOMIN and Botox
Efficacy: Adult Cervical Dystonia XEOMIN vs Botox7

Similar improvement from baseline in TWSTRS severity score

See the Full Study Details
Efficacy: Adult Blepharospasm XEOMIN vs Botox8

Similar improvement from baseline in JRS sum score

See the Full Study Details
Safety results were comparable between products, with no new or unexpected safety signals

XEOMIN Has Demonstrated Similar Duration of Effect to Botox

Duration of effect: XEOMIN vs active comparator (Botox)

In noninferiority studies comparing XEOMIN with Botox in adult patients with cervical dystonia or blepharospasm, days to onset of effect and days of duration of effect were similar for the 2 treatments.7,8

The corner rope of a boxing ring. This is meant to symbolize the duration of effect for XEOMIN when compared to Botox
Adult Cervical Dystonia – Onset and Duration After Treatment7
Adult Cervical Dystonia – Onset and Duration After Treatment8
See the Full Study Details
Adult Blepharospasm – Onset and Duration After Treatment8
See the Full Study Details

Safety results were comparable between products, with no new or unexpected safety signals

See the Indications

§ Patient-reported outcome: onset and waning of effect were subjectively estimated by the patient at control and end-of-study visits.

‡ Investigator assessment of duration of effect was calculated based on the time between the initial injection and the end-of-study visit (return to 80% of baseline TWSTRS severity score).

|| Duration of effect was calculated based on the time between the initial injection and the end-of-study visit (when the subject and the investigator agreed that a new injection was needed).

The potency Units of XEOMIN are specific to the preparation and assay method utilized. They are not interchangeable with the other preparations of botulinum toxin products and, therefore, Units of biological activity of XEOMIN cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method.

TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale; JRS, Jankovic Rating Scale.

References

  1. Carr WW, Jain N, Sublett JW. Immunogenicity of botulinum toxin formulations: potential therapeutic implications.  Adv Ther. 2021;38(10):5046-5064.
  2. Frevert J. Content of botulinum neurotoxin in Botox®/Vistabel®, Dysport®/Azzalure®, and Xeomin®/Bocouture®. Drugs R D. 2010;10(2):67-73.
  3. Frevert J. Pharmaceutical, biological, and clinical properties of botulinum neurotoxin type A products. Drugs R D. 2015;15(1):1-9.
  4. Walter U, Mühlenhoff C, Benecke R, et al. Frequency and risk factors of antibody-induced secondary failure of botulinum toxin therapy. Neurology. 2020;94(20):e2109-e2120.
  5. Kerscher M, Wanitphakdeedecha R, Trindade de Almeida A, Maas C, Frevert J. IncobotulinumtoxinA: a highly purified and precisely manufactured botulinum neurotoxin type A. J Drugs Dermatol. 2019;18(1):52-57.
  6. XEOMIN® [Package insert]. Raleigh, NC: Merz Pharmaceuticals, LLC; 2024.
  7. Benecke R, Jost WH, Kaňovský P, Ruzicka E, Comes G, Grafe S. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology. 2005;64(11):1949-1951.
  8. Roggenkämper P, Jost WH, Bihari K, Comes G, Grafe S; NT 201 Blepharospasm Study Team. Efficacy and safety of a new botulinum toxin type A free of complexing proteins in the treatment of blepharospasm.  J Neural Transm (Vienna). 2006;113(3):303-312.
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IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNING
WARNING:
DISTANT SPREAD OF TOXIN EFFECT

See full prescribing information for complete BOXED WARNING.

The effects of XEOMIN and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults, particularly in those patients who have underlying conditions that would predispose them to these symptoms.

INDICATIONS

XEOMIN® (incobotulinumtoxinA) for injection is indicated for the treatment of:

  • Chronic sialorrhea in patients 2 years of age and older
  • Upper limb spasticity in adults
  • Upper limb spasticity in pediatric patients 2 to 17 years of age, excluding spasticity caused by cerebral palsy
  • Cervical dystonia in adults
  • Blepharospasm in adults
IMPORTANT SAFETY INFORMATION (continued)
CONTRAINDICATIONS
  • Known hypersensitivity to any botulinum toxin product or to any of the components (human albumin, sucrose) in the formulation.
  • Infection at the proposed injection site(s) because it could lead to severe local or disseminated infection.
WARNINGS AND PRECAUTIONS
  • The potency units of XEOMIN are specific to the preparation and assay method utilized. Units of biological activity of Xeomin cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method.
  • Serious hypersensitivity reactions (anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea) have been reported with botulinum toxin products. If serious and/or immediate hypersensitivity reactions occur, discontinue further injection of XEOMIN and institute appropriate medical therapy immediately.
  • Treatment with XEOMIN and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these complications. When distant effects occur, additional respiratory muscles may be involved. Patients may require immediate medical attention should they develop problems with swallowing, speech, or respiratory disorders. Dysphagia may persist for several months, which may require use of a feeding tube. Aspiration may result from severe dysphagia.
  • Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) may be at increased risk for severe dysphagia and respiratory compromise from typical doses of XEOMIN.
  • Cervical Dystonia: Treatment with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been post- marketing reports of serious breathing difficulties, including respiratory failure, in patients with cervical dystonia treated with botulinum toxin products. Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscles are at greater risk of dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may decrease the occurrence of dysphagia.
  • Blepharospasm: Reduced blinking from injection of botulinum toxin products into the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders. Patients with previous eye surgery should be carefully assessed for corneal sensation before treatment. Xeomin should be used with caution in patients at risk of developing narrow angle glaucoma. To decrease the risk for ectropion, XEOMIN should not be injected into the medial lower eyelid area.
  • XEOMIN contains human serum albumin. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD). No cases of transmission of viral diseases, CJD, or vCJD have ever been reported for licensed albumin or albumin contained in other licensed products.
  • Use caution when XEOMIN is used where the targeted muscle shows excessive weakness or atrophy.
  • Use caution when XEOMIN is used in patients who have marked facial asymmetry, with surgical alterations to the facial anatomy, pre-existing eyelid or eyebrow ptosis, when excessive weakness or atrophy is present in the target muscles, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin (e.g., the inability to substantially lessen glabellar lines even by physically spreading them apart).
ADVERSE REACTIONS

The most commonly observed adverse reactions at rates specified below and greater than placebo are:

  • Chronic Sialorrhea:
    • in adults (≥4% of patients): tooth extraction, dry mouth, diarrhea, and hypertension.
    • in pediatric patients (≥1% of patients): bronchitis, headache, and nausea/vomiting.
  • Upper Limb Spasticity
    • in adults (≥2% of patients): seizure, nasopharyngitis, dry mouth, and upper respiratory tract infection.
    • in pediatric patients (≥3% of patients): nasopharyngitis and bronchitis.
  • Cervical Dystonia in adults (≥5% of patients): dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain.
  • Blepharospasm in adults (≥10% of patients): eyelid ptosis, dry eye, visual impairment, and dry mouth.
DRUG INTERACTIONS

Co-administration of XEOMIN and aminoglycoside or other agents interfering with neuromuscular transmission, (e.g., muscle relaxants), should only be performed with caution as these agents may potentiate the effect of the toxin.

Use of anticholinergic drugs after administration of XEOMIN may potentiate systemic anticholinergic effects.

The effect of administering different botulinum toxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of XEOMIN.

USE IN PREGNANCY

XEOMIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

PEDIATRIC USE

Safety and effectiveness of XEOMIN have not been established in pediatric patients for lower limb spasticity, cervical dystonia, or blepharospasm.

Safety and effectiveness have been established in pediatric patients 2 to 17 years of age in patients with chronic sialorrhea and upper limb spasticity. A pediatric assessment for XEOMIN in upper limb spasticity demonstrates that XEOMIN is safe and effective in another pediatric population. However, XEOMIN is not approved for such patient population due to marketing exclusivity for another botulinum toxin.

Visit www.xeomin.com to obtain the Full Prescribing Information and Medication Guide.

IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNING
WARNING:
DISTANT SPREAD OF TOXIN EFFECT

See full prescribing information for complete BOXED WARNING.

The effects of XEOMIN and all botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects. These symptoms have been reported hours to weeks after injection. Swallowing and breathing difficulties can be life threatening and there have been reports of death. The risk of symptoms is probably greatest in children treated for spasticity but symptoms can also occur in adults, particularly in those patients who have underlying conditions that would predispose them to these symptoms.

INDICATIONS

XEOMIN® (incobotulinumtoxinA) for injection is indicated for the treatment of:

  • Chronic sialorrhea in patients 2 years of age and older
  • Upper limb spasticity in adults
  • Upper limb spasticity in pediatric patients 2 to 17 years of age, excluding spasticity caused by cerebral palsy
  • Cervical dystonia in adults
  • Blepharospasm in adults
IMPORTANT SAFETY INFORMATION (continued)
CONTRAINDICATIONS
  • Known hypersensitivity to any botulinum toxin product or to any of the components (human albumin, sucrose) in the formulation.
  • Infection at the proposed injection site(s) because it could lead to severe local or disseminated infection.
WARNINGS AND PRECAUTIONS
  • The potency units of XEOMIN are specific to the preparation and assay method utilized. Units of biological activity of Xeomin cannot be compared to or converted into Units of any other botulinum toxin products assessed with any other specific assay method.
  • Serious hypersensitivity reactions (anaphylaxis, serum sickness, urticaria, soft tissue edema, and dyspnea) have been reported with botulinum toxin products. If serious and/or immediate hypersensitivity reactions occur, discontinue further injection of XEOMIN and institute appropriate medical therapy immediately.
  • Treatment with XEOMIN and other botulinum toxin products can result in swallowing or breathing difficulties. Patients with pre-existing swallowing or breathing difficulties may be more susceptible to these complications. When distant effects occur, additional respiratory muscles may be involved. Patients may require immediate medical attention should they develop problems with swallowing, speech, or respiratory disorders. Dysphagia may persist for several months, which may require use of a feeding tube. Aspiration may result from severe dysphagia.
  • Individuals with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular junctional disorders (e.g., myasthenia gravis or Lambert-Eaton syndrome) may be at increased risk for severe dysphagia and respiratory compromise from typical doses of XEOMIN.
  • Cervical Dystonia: Treatment with botulinum toxins may weaken neck muscles that serve as accessory muscles of ventilation. This may result in critical loss of breathing capacity in patients with respiratory disorders who may have become dependent upon these accessory muscles. There have been post- marketing reports of serious breathing difficulties, including respiratory failure, in patients with cervical dystonia treated with botulinum toxin products. Patients with smaller neck muscle mass and patients who require bilateral injections into the sternocleidomastoid muscles are at greater risk of dysphagia. Limiting the dose injected into the sternocleidomastoid muscle may decrease the occurrence of dysphagia.
  • Blepharospasm: Reduced blinking from injection of botulinum toxin products into the orbicularis muscle can lead to corneal exposure, persistent epithelial defect, and corneal ulceration, especially in patients with VII nerve disorders. Patients with previous eye surgery should be carefully assessed for corneal sensation before treatment. Xeomin should be used with caution in patients at risk of developing narrow angle glaucoma. To decrease the risk for ectropion, XEOMIN should not be injected into the medial lower eyelid area.
  • XEOMIN contains human serum albumin. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases and variant Creutzfeldt-Jakob disease (vCJD). There is a theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD). No cases of transmission of viral diseases, CJD, or vCJD have ever been reported for licensed albumin or albumin contained in other licensed products.
  • Use caution when XEOMIN is used where the targeted muscle shows excessive weakness or atrophy.
  • Use caution when XEOMIN is used in patients who have marked facial asymmetry, with surgical alterations to the facial anatomy, pre-existing eyelid or eyebrow ptosis, when excessive weakness or atrophy is present in the target muscles, excessive dermatochalasis, deep dermal scarring, thick sebaceous skin (e.g., the inability to substantially lessen glabellar lines even by physically spreading them apart).
ADVERSE REACTIONS

The most commonly observed adverse reactions at rates specified below and greater than placebo are:

  • Chronic Sialorrhea:
    • in adults (≥4% of patients): tooth extraction, dry mouth, diarrhea, and hypertension.
    • in pediatric patients (≥1% of patients): bronchitis, headache, and nausea/vomiting.
  • Upper Limb Spasticity
    • in adults (≥2% of patients): seizure, nasopharyngitis, dry mouth, and upper respiratory tract infection.
    • in pediatric patients (≥3% of patients): nasopharyngitis and bronchitis.
  • Cervical Dystonia in adults (≥5% of patients): dysphagia, neck pain, muscle weakness, injection site pain, and musculoskeletal pain.
  • Blepharospasm in adults (≥10% of patients): eyelid ptosis, dry eye, visual impairment, and dry mouth.
DRUG INTERACTIONS

Co-administration of XEOMIN and aminoglycoside or other agents interfering with neuromuscular transmission, (e.g., muscle relaxants), should only be performed with caution as these agents may potentiate the effect of the toxin.

Use of anticholinergic drugs after administration of XEOMIN may potentiate systemic anticholinergic effects.

The effect of administering different botulinum toxin products at the same time or within several months of each other is unknown. Excessive neuromuscular weakness may be exacerbated by administration of another botulinum toxin prior to the resolution of the effects of a previously administered botulinum toxin.

Excessive weakness may also be exaggerated by administration of a muscle relaxant before or after administration of XEOMIN.

USE IN PREGNANCY

XEOMIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

PEDIATRIC USE

Safety and effectiveness of XEOMIN have not been established in pediatric patients for lower limb spasticity, cervical dystonia, or blepharospasm.

Safety and effectiveness have been established in pediatric patients 2 to 17 years of age in patients with chronic sialorrhea and upper limb spasticity. A pediatric assessment for XEOMIN in upper limb spasticity demonstrates that XEOMIN is safe and effective in another pediatric population. However, XEOMIN is not approved for such patient population due to marketing exclusivity for another botulinum toxin.

Visit www.xeomin.com to obtain the Full Prescribing Information and Medication Guide.